Rbm8a deficiency causes hematopoietic defects by modulating Wnt/PCP signaling.

Autor:	Kocere A; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland., Chiavacci E; Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland., Soneson C; Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.; SIB Swiss Institute of Bioinformatics, University of Zürich, Zürich, Switzerland., Wells HH; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Méndez-Acevedo KM; Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin-Buch, Germany., MacGowan JS; Center for Precision Environmental Health and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Jacobson ST; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Hiltabidle MS; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Raghunath A; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA., Shavit JA; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA., Panáková D; Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin-Buch, Germany.; University Hospital Schleswig Holstein, Kiel, Germany.; German Centre for Cardiovascular Research (DZHK), partner site Hamburg, Kiel, Lübeck, Germany., Williams MLK; Center for Precision Environmental Health and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Robinson MD; Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.; SIB Swiss Institute of Bioinformatics, University of Zürich, Zürich, Switzerland., Mosimann C; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Burger A; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 01. Date of Electronic Publication: 2024 Feb 01.
DOI:	10.1101/2023.04.12.536513
Abstrakt:	Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function for RBM8A/Y14 that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafish rbm8a perturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell re-arrangements. In hypomorphic rbm8a zebrafish, we observe a significant reduction of cd41 -positive thrombocytes. rbm8a -mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish that rbm8a -mutant embryos show convergent extension defects and that reduced rbm8a function interacts with perturbations in non-canonical Wnt/PCP pathway genes w nt5b , wnt11f2 , fzd7a , and vangl2 . Using live-imaging, we found reduced rbm8a function impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants for rbm8a and for the PCP gene vangl2 feature impaired expression of early hematopoietic/endothelial genes including runx1 and the megakaryocyte regulator gfi1aa . Together, our data propose aberrant LPM patterning and hematopoietic defects as consequence of attenuated non-canonical Wnt/PCP signaling upon reduced rbm8a function. These results also link TAR Syndrome to a potential LPM origin and a developmental mechanism. Competing Interests: COMPETING INTERESTS STATEMENT J.A.S. has been a consultant for Sanofi, Takeda, Genentech, CSL Behring, and HEMA Biologics.
Databáze:	MEDLINE
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